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Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.
The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.
Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.
The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.
Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).
The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.
The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).
The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.
In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.
Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).
Although the studies described here have established the capacity for large, multicenter trials across disease-endemic countries, the design and selection of future experimental regimens will need to incorporate a triage process that can mitigate risks while enabling the accelerated development of much-needed treatment-shortening therapies. The disconnect between the phase II data that motivated these trials and the phase III results reinforces the idea that small sample sizes limit the utility of short trials in predicting the success of treatment-shortening regimens.
As these three trials have confirmed, our understanding of the science underlying positive clinical outcomes remains rudimentary. It’s time to go back to basics.
Digby F. Warner, Ph.D., and Valerie Mizrahi, Ph.D., are in the molecular mycobacteriology research unit at the Institute of Infectious Disease and Molecular Medicine, Cape Town and in the department of clinical laboratory sciences at the University of Cape Town, both in South Africa. Dr. Warner reported receiving funding from the South African Medical Research Council, Medical Research Foundation South Africa, and Wellcome Trust. Dr. Mizrahi reported funding from the European & Developing Countries Clinical Trials Partnership, the Bill and Melinda Gates Foundation, the Wellcome Trust, and USAID. Dr. Mizrahi also serves on the scientific advisory committee of the Global Alliance for TB Drug Development, which supported Dr. Gillespie’s study. This comment is excerpted from an editorial by Dr. Warner and Dr. Mizrahi that accompanied the three reports (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMe1410977]).
Although the studies described here have established the capacity for large, multicenter trials across disease-endemic countries, the design and selection of future experimental regimens will need to incorporate a triage process that can mitigate risks while enabling the accelerated development of much-needed treatment-shortening therapies. The disconnect between the phase II data that motivated these trials and the phase III results reinforces the idea that small sample sizes limit the utility of short trials in predicting the success of treatment-shortening regimens.
As these three trials have confirmed, our understanding of the science underlying positive clinical outcomes remains rudimentary. It’s time to go back to basics.
Digby F. Warner, Ph.D., and Valerie Mizrahi, Ph.D., are in the molecular mycobacteriology research unit at the Institute of Infectious Disease and Molecular Medicine, Cape Town and in the department of clinical laboratory sciences at the University of Cape Town, both in South Africa. Dr. Warner reported receiving funding from the South African Medical Research Council, Medical Research Foundation South Africa, and Wellcome Trust. Dr. Mizrahi reported funding from the European & Developing Countries Clinical Trials Partnership, the Bill and Melinda Gates Foundation, the Wellcome Trust, and USAID. Dr. Mizrahi also serves on the scientific advisory committee of the Global Alliance for TB Drug Development, which supported Dr. Gillespie’s study. This comment is excerpted from an editorial by Dr. Warner and Dr. Mizrahi that accompanied the three reports (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMe1410977]).
Although the studies described here have established the capacity for large, multicenter trials across disease-endemic countries, the design and selection of future experimental regimens will need to incorporate a triage process that can mitigate risks while enabling the accelerated development of much-needed treatment-shortening therapies. The disconnect between the phase II data that motivated these trials and the phase III results reinforces the idea that small sample sizes limit the utility of short trials in predicting the success of treatment-shortening regimens.
As these three trials have confirmed, our understanding of the science underlying positive clinical outcomes remains rudimentary. It’s time to go back to basics.
Digby F. Warner, Ph.D., and Valerie Mizrahi, Ph.D., are in the molecular mycobacteriology research unit at the Institute of Infectious Disease and Molecular Medicine, Cape Town and in the department of clinical laboratory sciences at the University of Cape Town, both in South Africa. Dr. Warner reported receiving funding from the South African Medical Research Council, Medical Research Foundation South Africa, and Wellcome Trust. Dr. Mizrahi reported funding from the European & Developing Countries Clinical Trials Partnership, the Bill and Melinda Gates Foundation, the Wellcome Trust, and USAID. Dr. Mizrahi also serves on the scientific advisory committee of the Global Alliance for TB Drug Development, which supported Dr. Gillespie’s study. This comment is excerpted from an editorial by Dr. Warner and Dr. Mizrahi that accompanied the three reports (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMe1410977]).
Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.
The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.
Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.
The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.
Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).
The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.
The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).
The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.
In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.
Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).
Three different short-course treatment regimens for tuberculosis failed to show noninferiority to the standard 6-month course in separate phase III randomized clinical trials, even though the experimental regimens produced a more rapid decline in bacterial load, as expected, according to reports published online Oct. 23 in the New England Journal of Medicine.
The main reason that the short-course (4-month) approaches failed to measure up to standard treatment was that, despite their greater bactericidal activity, the rate of relapse was excessive after treatment was completed.
Researchers undertook these large international trials because the data from several phase II and murine studies had been so promising: replacing either the isoniazid or the ethambutol in the standard anti-TB regimen with a fluoroquinolone appeared to permit shortening of the treatment period without sacrificing efficacy. But the consistently negative results from these phase III studies clearly demonstrate that this approach is not effective.
The first trial involved 1,931 adults with newly diagnosed and untreated Mycobacterium tuberculosis infection who were treated in South Africa, India, Tanzania, Kenya, Thailand, Malaysia, Zambia, China, and Mexico. These patients were randomly assigned to receive the standard regimen of isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid plus rifampin (control group, 640 participants); or an experimental regimen in which ethambutol was replaced by moxifloxacin for 17 weeks, followed by 9 weeks of placebo (655 participants); or an experimental regimen in which isoniazid was replaced by moxifloxacin in the same way (636 participants), said Dr. Stephen H. Gillespie of the University of St. Andrews (England) and University College London and his associates.
Patients in the two experimental groups converted to culture-negative status more rapidly than did those in the control group. However, in a per-protocol analysis, 92% of the control group achieved a favorable final outcome, compared with only 85% and 80% of the experimental groups, respectively. Results of a modified intention-to-treat analysis and of more than 20 sensitivity analyses showed the same pattern. At the end of active treatment, only 12 patients in the control group had a relapse of TB infection, compared with 64 patients and 46 patients, respectively, in the experimental groups, Dr. Gillespie and his colleagues said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1407426]).
The second trial was an open-label noninferiority study involving 1,836 patients in Benin, Guinea, Kenya, Senegal, and South Africa. They were randomly assigned to standard 6-month treatment (919 control subjects) or an experimental treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months (917 patients), said Dr. Corinne S. Merle of the London School of Hygiene and Tropical Medicine and her associates.
The primary efficacy endpoint, the percentage of patients with an unfavorable outcome after 24 months, was 17.2% in the control group and 21.0% in the experimental group, a significant difference. In particular, more than twice as many patients in the experimental group (14.6%) had a relapse than in the control group (7.1%). As with Dr. Gillespie’s study, Dr. Merle’s study failed to show that the short-course regimen was noninferior to the standard regimen. Again, “the expectations raised by [phase I and II trials] were not borne out in this phase III trial,” they said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1315817]).
The third trial, involving 827 patients in South Africa, Zimbabwe, Botswana, and Zambia, compared the standard control regimen against a 4-month regimen in which isoniazid was replaced by moxifloxacin and a 6-month regimen in which isoniazid was replaced by moxifloxacin, said Dr. Amina Jindani of St. George’s University of London and University College London and her associates.
In the per-protocol analysis, unfavorable outcomes occurred in 4.9% of the control group and 3.2% of the 6-month experimental group, compared with 18.2% of the short-course experimental group. The corresponding figures for the intention-to-treat analysis were 14.4%, 13.7%, and 26.9%, respectively.
Again, this discrepancy was attributed primarily to the significantly higher relapse rate in the short-course, compared with the control treatments – 26 cases with 4 months of treatment vs. 5 cases each with 6 months, Dr. Jindani and her associates said (N. Engl. J. Med. 2014 Oct. 23 [doi:10.1056/NEJMoa1314210]).
Key clinical point: Shortening tuberculosis treatment to 4 months is not proven to be effective in three phase III studies.
Major finding: Relapse was seen in more than twice as many patients (14.6%) receiving treatment in which gatifloxacin was substituted for ethambutol and the course of therapy was shortened to 4 months in lieu of the standard 6-month treatment (7.1%).
Data source: An open-label noninferiority study involving 1,836 patients.
Disclosures: The researchers reported no relevant financial conflicts.
